Parenteral aureomycin in anhydrous form



Patented July 7, 1953 UNITED STATES PATENT OFFICE IN AltlHYDROUS,

Joseph: Weidenheimer, Pearl River, and Lawrcnce.-Rittel:,, Spring Valley, N Y., assignors to Amerieanfiyanamid Company, New York, N. Y., a cqrporati'oncfMaine Net-Drawing: ApplicationSeptember'8, 1949; Serial; No. 114,695-

I Our invention relate atoa new; therapeutic composition. more particularly totherapeutic agents, comprising; aureomycin as; anv acid salt; in associationv with a materialwhich modifies the pH of aqueous solutions thereof; toamoresuitable range, for parenteral, use. Aureomycinis a new drug produced by the fermentation ofv a nutrient liquor. by-thaiungus Strezgtomz/ces:aureojacz'ens as: is more particularly described. and

set: forth in. the; co-pending; applicatiom of, Benjamin M. Duggar- Serial; Numben 7 5,92 filed February 11, 1948, now PatentNumben2A82-,055 dated; September; 13, 1M9.

Aureomycin has been found: to. bea a; naphthacenev derivative and while having; a. structure which stron ly suggests tautomeric forms; isrbelieved to exist with the following probable:strucr turezzof: an; acid: or; basea Aureomycin: iszmore' stable at a lower pH and is most commonly used-iasan acidsalt; usually the-hydrochloride; Inathe past it has been. found; thatrth'e: hydrochloridessalt maybezadministeredfeither; orallyror parenterally, but for parenteral use the high acidity of the aqueous, solutionv is: notausua-lly desirable: Similarly, the free base and metallic salt are not.

sufficiently soluble and stable in aqueous-solutions to: be satisfactory for administration.-

We havefoundthateven' thoug-h aureomycin is comparatively unstable at the pH ranges most desirable for parenteral administration, as a dry powder it is sufficiently stable in the presence of sufiicient of an amino acid buffer, also as a dry material, to be salabl'eas such. The mixture or thedrypowders may be. stored withoutretrigeration: under normal conditions; for a; prolongedperiod. When. water; is added to=it, the material dissolvesand; the aminoacid buffer serves-to aid informing a solution with. a pH satisfactory for parenteral use which may bethereupon. injected into a patient. This aqueous: material is; not stable over prolonged periods. and: is: best used immediately afterthe: addition ofv the water it being preferred"; that ritbe injected: within a .period. of less than. 3.0 minutes. About-itenpercent inactivation occurs in 3.O.-minutes;at normaltemiperatures; I Aureomycin as; the:- hydrochlorida, when; dis solved in water, normally is found to havev apH in the neighborhood .of- 2.5 to 3 at a concentration of. around 10, milligrams per cc. The pH of. solutions preparedi'from' thedTyymiXtures: of

aureomycin as, its hydrochloride and" an' amino acid bufier system includingsodium: glycinat'e, isin the neighborhood of 7 to 10; depending upon the choice of the. amino acid, an'd'other conditions. The alkali metal; salts of other amino acids, such as asparagine, alanine; hydroxyproline, leucine, norleucine, etc. may also be used as the amino acid buffer. It is necessary that the amino acid be reasonably: soluble and that its bufiering action bev near the desired range; Amino acids whose isoelectric' point: is between approximately BIB-and 6.2 are satisfac tory: The amino acids which are='water'soluble and whose alkali metal salts ex-hibit a buffer ac tion' from about 8.5to -about*10; are satisfactory as they form solutions with aureomycinih the permissible pH range iorinjection of from about 7:130 9.. I I 5 Itisof course. possible touseprepara-tionsin which thereare slight-variationsa'from the-pretferred values,-, and obtain satisfactoryresultsi The .aureomycin may be used-as its hydrochloride or other hydrohalide salt, or other; crystalline acid 1 salt, The. amino 1 acid is preferably used as its sodium. salt although; itmay be used a'ssthe potassium. salt. or otherysalt providedthattthe additional cations-introduced are not'deleteriou's: Thesodium salt'is usually-the. cheapest; an'dithe most readilyv obtained; ,and in the absence-of; 1111':- usual conditions 'willbe found to be most satisfactory. Amino acids themselves are generally innocuous on: parenteralinjection; so thatfree amino acids may be present and make up part of the buffer system within solubility and pH limits.

For best results it is necessary that the ma terials remain dry because in the presence of water the pH is at an undesirably high level for best stability. In the absence of water the material is storage stable and may in fact be heat sterilized. The quantity of the amino acid to be added may vary over rather wide limits but excellent results are obtained when from 2 to 3 moles of the amino acid salt are present per mole of aureomycin hydrochloride.

Aureomycin hydrochloride is more soluble in the amino acid builer system than it is in water. This enables the administration of a therapeutic dose in a smaller quantity of fluid, a further advantage of the invention.

The following examples illustrate but do not limit the range over which a therapeutically useful product may be obtained, but they do show examples of highly satisfactory therapeutic products.

Example 1 1 gram of recrystallized aureomycin hydrochloride was finely ground and screened, then mixed with 2.5 mole equivalents (454 milligrams) of dry powdered sodium glycinate, the commercial product being used. The powders were mixed and filled into vials which were heat sterilized and then capped. When the powders were constituted to a concentration of 50 milligrams of aureomycin hydrochloride per milliliter, a clear satisfactory solution was obtained having a pH of 8.3. The thus obtained solution is satisfactory for use by injection into the body. If allowed to stand for 30 minutes at room temperature as much as 10% of the aureomycin may be inactivated.

Example 2 1 gram of recrystallized aureomycin hydrochloride was ground, screened and mixed with 2 mole equivalents of sodium glycinate (364 milligrams). Upon solution in water to a concentration of 50 milligrams of aureomycin hydrochloride per milliliter, a clear solution was obtained with a pH between 7.8 and 7.9. The solution may reprecipitate on standing.

Example 3 1 gram of dry powdered aureomycin hydrochloride was mixed with 3 mole equivalents (546 milligrams) of sodium glycinate. The mixture was heat sterilized, then sealed in vials. For use, it was dissolved by the addition of 20 milliliters of sterile water, thereby yielding a clear solution suitable for parenteral use, having a pH of about 8.8.

Example 4 Example 5 1 gram of aureomycin hydrochloride was finely ground and mixed with 1.32 grams of the sodium salt of 1(-)-leucine and the mixture heat sterilized and sealed in vials. Upon use, 50 milliliters of water were added to provide a 2% solution of aureomycin computed as the hydrochloride which was clear and stable for short periods. The pH was approximately 8 although upon repetition it was found this varied between various lots.

As our invention we claim:

1. An aureomycin preparation in anhydrous form capable of yielding an intravenously administrable solution on solution in water comprising as a powder an unreacted mixture of aureomycin hydrochloride and about 2.5 mole equivalents of sodium glycinate.

2. An aureomycin preparation of improved characteristics comprising as a powder an anhydrous unreacted mixture of a non-toxic, intravenously acceptable acid salt or aureomycin and from 2 to 3 mole equivalents of an alkali metal salt of a soluble amino acid whose isoelectric point is between approximately 5.8 and 6.2.

3. An aureomycin preparation of improved characteristics comprising as a powder an anhydrou unreacted mixture of aureomycin hydrochloride and from 2 to 3 mole equivalents of sodium glycinate.

4. An aureomycin preparation of improved characteristics comprising as a powder an anhydrous unreacted mixture of aureomycin hydrochloride and from 2 to 3 mole equivalents of the sodium salt of leucine.

5. An aureomycin preparation of improved characteristics comprising as a powder an anhydrou unreacted mixture of aureomycin hydrochloride and from 2 to 3 mole equivalents of the sodium salt of asparagine.

6. A composition in anhydrous form capable of yieldin an intravenously administrable aureomycin-containing solution on dilution with water comprising an intravenously acceptable acid salt of aureomycin and an alkali metal salt of a soluble amino acid whose isoelectric point is between approximately 5.8 and 6.2 in an amount sufficient so that the pH of the solution formed on dilution with water is between pH 7 and 9.

JOSEPH F. WEIDENHEIMER. LAWRENCE RIT'IER.

References Cited in the file of this patent UNITED STATES PATENTS Name Date Roberts Mar. 10, 1942 Abramson et al Mar. 7, 1944 Duggar Sept. 13, 1949 Pillemer Nov. 7, 1950 OTHER REFERENCES Number 

1. AN AUREOMYCIN PREPARATION IN ANHYDROUS FORM CAPABLE OF YIELDING AN INTRAVENOUSLY ADMINISTRABLE SOLUTION ON SOLUTION IN WATER COMPRISING AS A POWDER AN UNREACTED MIXTURE OF AUREOMYCIN HYDROCHLORIDE AND ABOUT 2.5 MOLE EQUIVALENTS OF SODUIM GLYCINATE. 